Reduced immune response in elderly population contributes to increased frequency of infection and lack of responses against vaccination. Vulnerability of the elderly to novel type of virus and agents of bioterrorism raises significance of understanding the mechanism by which immune response is suppressed by aging. Our previous study showed that T cells that mature from young mouse bone marrow stem cells in the aged host mice have severe impairment in their responsiveness. These T cells recapitulated phenotypes of normally aged mouse T cells. On the other hand, T cells derived from aged mouse bone marrow stem cells, when differentiated in the young mouse environment, were responsive to stimuli as well T cells derived from young mouse bone marrow stem cells. The data suggested that the internal environment of aged mouse plays a critical role in impairment of T cell responses. In aged mice, it was also reported that the frequency of Foxp3+ regulatory T cells (Tregs) is higher than in young mice. Tregs are not only important for preventing autoimmune disease but also play critical roles in establishment of chronic infection by various agents. Thus, increase of regulatory T cells may be a factor that causes reduced immune responses in the aged population. We have recently demonstrated that inhibition of phospholipase D (PLD) signaling in T cells causes selective enrichment of Tregs. Inhibition of PLD signaling causes severe inhibition of antigen responses by T cells. Moreover, PLD signaling has been shown to be sensitive to membrane lipid composition. Based on these data, we hypothesize that T cell responses in aged population are impaired by reduction of PLD signaling. Such reduction can affect responsiveness of effector T cells and change the balance between Tregs and non-Tregs toward the dominance by Tregs. We will determine if PLD signal inhibition is imposed by the internal environment of aged mice. This project will help understanding the mechanism by which aging impairs the function of the immune system. The main object of this research is to determine the effect of aging on the balance between a group of lymphocytes called regulatory T cells and others. Regulatory T cells play pivotal roles in prevention of autoimmune disease but also suppress immunity against infection and cancer. Our data show that the internal environment of aged mouse may increase the frequency of regulatory cells. We will determine the factor that causes such imbalance of immune cells in the elderly in this study. [unreadable] [unreadable] [unreadable]